The accuracy and precision of the analytical data from the analysis of liquid samples with high matrix load often suffer from a compromised performance of the sample introduction system. This is especially significant in the case of miniaturized, pneumatic low flow nebulizers. Alternative low-flow sampling devices based on different operating principles are imperative to overcome this drawback. The superior performance of such an alternative liquid sample introduction system for ICP-MS, the drop-on-demand (DOD) aerosol generator based on thermal inkjet technology, was recently outlined by the same group for the analysis of aqueous standard solutions. Current improvements of the system now allow for the independent operation of two sampling nozzles, which expands the system capabilities to independently dosing two liquids simultaneously into the carrier gas stream of an ICP-MS. The applicability of the proposed dual-DOD (dDOD) ICP-MS method to the analysis of real urine samples is outlined. Its susceptibility to matrix effects was studied through 2-dimensional ion distributions within the ICP for different matrices. A new calibration strategy for ICP-MS based on the dosing frequencies of the dDOD (dosing frequency-based calibration, DFC) and its application to trace metal analysis in micro-volumes of real samples with high matrix content are presented. Using this method Li, Sr, Mo, Sb and Cs were accurately determined in the concentration range of 8–122 μg L−1 in urine reference material. The advantages of the DFC, e.g. minimum sample and analysis time consumption, are outlined and the quality of the achievable results with respect to accuracy and precision is critically discussed. All analytical data are compared to those obtained with a conventional MicroMist nebulization system in combination with ICP-MS using classic calibration procedures.